Opioid dependence (OD) is a common, chronic, relapsing addiction with a substantial genetic component. Central to the neurobiology of OD is the mu opioid receptor (MOR), through which most of the rewarding effects of opioids are mediated. The goal of this project is to enhance our understanding of MOR in OD through linkage disequilibrium (LD) genetics studies of OD, using novel candidate genes, MOR interacting proteins (MORIPs). Using existing MORIPs as well as novel ones identified through Project One, we will conduct a case-control LD analysis of these known MORIPs and newly-defined MORIPs. DMA samples and clinical information from ~ 2000 OD individuals, whose data and biopecimens are in a central NIDA repository. In addition, we have access to ~ 4500 control DNA samples and clinical information from an NIMH repository. Using these resources, MORIP genes and possibly other novel candidates will be assessed for roles in genetic susceptibility to OD. Any MORIP genes whose alleles are in LD with OD will be subject to resequencing in ~ 200 OD DNA samples to detect uncommon variants which may have a large impact on OD risk. Haplotypes/alleles in LD with OD will be studied in tissue culture and post-mortem brain experiments to determine the influence of the risk haplotype on gene transcription and/or translation. Through this project, our understanding of the role of MOR in OD will be enhanced, opening new avenues for treatment of this common and severe addiction.